Tertiary alcohol derivatives of 8-alkylnortropanes and the acid and quaternary ammonium salts thereof



neurotics.

United States Patent TERTIARY ALCOHOL DERIVATIVES 0F 8-ALKYL- NORTROPANES AND THE ACID AND QUATER- NARY AMMONIUM SALTS THEREOF Charles L. Zirkle, Haddon Heights, N. J., assignor to Smith, Kline & 'French Laboratories, Philaclelphia,Pa.,

a corporation of Pennsylvania No Drawing. Application July 1,1955, Serial,No. 519,64 9

6 Claims. (Cl. 260-492) This invention realtes to certain new physiologically active tertiary alcohol derivatives of 8.-alk ylnortropanes and the organic and inorganic salts thereof. It also relates to quaternary ammonium salts of these tertiary alcohol derivatives of 8-alkylnortropanes.

The new chemical compounds according to this .invention have utility, for example, for treating .the parasympathetic nervous system in providing, for example, antispasmodic and anticholinergic action .and further have utility as antiemetics and for treating the central nervous system, for example, for treating psychotics and psycho- The compounds-of this invention also have utility as intermediates for use in the'preparation of compounds having utility for treating the parasympathetic ,nervous system in providing, for example, antispasmodic and anticholinergic action and further having utility as antiemetics and for treating the central nervous system, for example, for treating psychotics and psychoneurotics. Where the salts are used for therapeutic purposes, it will 'be obvious to those skilled in the art to select a non-toxic salt.

The new compounds according to this invention have the structure shown by the following formula:

FORMULA 1 Il -N X in which: R is a straight or branched chain lower alkyl radical having preferably from :1 to 4 carbonatoms.

R2 :and R being selected from the group Qnsisting of straight or branched chain-lower alkyl groups having preferably from 1 ;to 6.carbon atoms, cyclqalkyl groups having from 5 to 6 carbon-atoms, cycloalleyhalkylihaving in which: 'R,R2 and R areas ,givenabove ,and is from 0 to '3, preferably 1.

2,800,481 Patented July :23, 1957 ICC Where hereinafter the symbols 'R, R2 and R3 andnare mentioned in the description, they will indicate the sub =stituents indicated for them in connection with the'abov general formulas. I

The organicand inorganic salts of the base 'of the above formulas contemplated by this inventionrinclude by way of example salts of the base formed with organic acids such as, for-example, tartaric, -maleic,.cam'phorsulfonic, citric, acetic, propionic,'butyric, succinic, glutaric, adipic, ascorbic, lactic, -levulinic,;malic, mandelic, cinna mic, gluconic, methanesulfonic, benzene sulfonic, fumaric, citraconic, itaconic, 'lauric, stearic, myristic, palmitic, 'linoleic, 'aspartic and sulfoacetic, and inorganic acids such as, for-example, hydrochloric, hydrobromic, sulfuric, -su1- famic, phosphoric, nitric, etc. and can readily be produced by reacting the free base withtheappropriate acid.

This invention also embraces quaternary ammonium salts formed with organic esters of sulfuric, hydrohalic and aromatic sulfonicacids. Exemplary of such esters are methyl chloride, methyl bromide, methyl iodide, ethyl chloride, propyl bromide, butyl chloride, 'isobutyl chloride, ethylene bromohydrin, ethylene chlorohydrin, a1lyl bromide, methallylbromide, crotyl bromide,.benzyl chloride, benzyl bromide, naphthylmethyl chloride, phenethyl bromide, dimethyl sulfate, diethyl sulfate, methyl benzene-sulfonate, ethyl toluene-sulfonate, and the like.

The quaternary ammonium salts will be prepared by :treating a solution of the base of the above structural formulas in a suitable solvent such as chloroform, acetone, benzene, toluene or ether with an excess of an organic ester of sulfuric, hydrohalic or aromatic sulfonic acid. This reaction will be'carried out most advantageously at'a temperature in the range of from about 25 C. to about C.

Compounds having the structure of Formula 2 maybe prepared by first producing a compound of the following structure:

FORMULA 3 in which: R is a straight or branched chain lower ;alkyl radical having preferably from 1 to 4 carbon atoms.

R1 is selected from the group consisting of hydrogen and a straight .or branched chain lower alkyl radical having preferably from 1 to 4 carbon atoms and n is from 0 1.0.

The comp nd o F m 3 may be a ious y P 1 duced'by Methods A through -D.

METHOD A The compounds of Formula 3 where n is 0 are obtained by the reaction sequence outlined-below:

' OH Fattyacld i 000R; All-hydride goon, V)

.3 to a temperature in the range of about 350 C. to about 500 C. furnishes the unsaturated ester (III). The saturated ester (IV, R1=lower alkyl) is obtained by hydrogenation of the unsaturated ester (III) using, for example, anoble metal catalyst such as platinum or palladium or a Raney nickel catalyst and at room temperature and atmospheric pressure or at elevated temperatures and pressures. The acid (IV, R1=I-I) is obtained as the hydro'chloride salt by-refluxing the saturated ester with an excess of hydrochloric acid and then removing the excess acid in vacuo. The thus formed acid is readily esterified to produce the ethyl, propyl, butyl esters, etc. using ethanol, propanol, butanol, etc. respectively.

METHOD B The preparation of the compounds of Formula 3 above where n is from 1'to 3 is illustrated for the preparation of these compounds where n=1 in the scheme below:

The carboxylic acid or ester (IV) is reduced to the carbinol (V) using, for example, lithium aluminum hydride, or in the case of the esters, using sodium-alcohol combinations, or catalytic hydrogenation. The halide (VI), in the form of its hydrochloride salt, is obtained from the reaction of (V) with excess thionyl chloride. The halide base (VI) is converted to the nitrile (VII) by reaction with sodium or potassium cyanide preferably in an aqueous alcohol medium. The acid (VIII, R1=H) and that in turn when this compound is subjected to the above reaction sequence a compound having the following structural formula will result:

METHOD C By way of further example, the compounds of Formula 3 above where n is 1 may also be readily made by the reaction sequence outlined below:

soot, CHzNi N 00011 R-N 0001 (VIII) R-N oooEN, R-N 0111000111 The hydrochloride of the amino acid (IX) is converted to the acid chloride hydrochloride (X) which in turn yields the diazoketone (XI) by reaction with a large excess of diazomethane. The diazoketone (XI) is converted in the presence of a suitable catalyst, as, for example, silver oxide and a suitable medium such as, for example, methanol, ethanol, propanol, or butanol, to form the ester (VIII). Where an aqueous medium is used the carboxylic acid (VIII) is produced. Similarly, the hydrochloride of the amino acid when used as the starting material in the above described reaction sequence will form the compounds of Formula 3 above where n=2. Similarly the hydrochloride of the compound of Formula 3 where n=2 can then in turn be used as the starting material in the reaction sequence given above to form the compounds of Formula 3 above where 11:3.

METHOD D The compounds of Formula 3 above where n=l may also be formed by the following reaction sequence:

OOOCzHb (X11) ('9 R-N 0 L mu (VIII) COOCzHs An N-alkyl-nor-tropinone (XII) is reacted with a lower alkyl ester of cyanoacetic acid such as methyl, ethyl or butyl, cyanoacetate (the ethyl ester being specifically illustrated above) using as a solvent, for example, a lower fatty acid such as propionic, acetic or butyric acid and preferably in the presence of a catalyst which is a salt of a weak acid and a weak base, for example, ammonium acetate. The thus formed unsaturated cyano ester is then hydrogenated at a temperature of about 40 C. to C. in the presence of a noble metal catalyst such as platinum or palladium to the N-lower alkyl-3-[(u-cyanoa-carbalkoxy)-methyl]-nortropane. Saturated cyano ester (XIII) is hydrolyzed and decarboxylated to 3(N-alkylnortropane) acetic acid by heating with an excess of a volatile mineral acid such as a hydrohalic acid such as hydrobromic or hydrochloric acid. The removal of the excess mineral acid by distillation in vacuo leaves the amino acid salt (VIII, R1=H) which can readily be esterified with a lower aliphatic alcohol in the presence of a strong acid, for example, a hydrohalic acid such as hydrochloric or hydrobromic acid, sulfuric acid or para toluenesulfonic acid.

The esters of Formula 3 may be used to produce the compounds of this invention as represented by Formula 2 where R2 and R3 are the same by reacting the esters of Formula 3 with the lithium or magnesium derivative prepared from lower alkyl bromides, cyclohexyl bromide, cyclopentyl bromide, cycloalkyl-alkyl bromides having from 6 to 10 carbon atoms, phenyl bromide, lower alkyl or lower alkoxy substituted phenyl bromides, 2-bromopyridine and 2-bromothiophene as illustrated 'by the following general scheme:

In general, it will be desirable to use the lithium derivative instead of the magnesium derivative, except in the case of cycloalkyl bromides, since the chief product using the orgauo magnesium reagent will usually be the corresponding ketone and the desired carbinol will be formed only in low yield. In carrying out this reaction, it advantageous to use a solvent si ijch as diethylether and to employ an excess of the organo-metallic reagent. The compounds of this invention having the formula (Formula 2) where R3 and R2 are the same or different can be prepared by utilizing the compounds of Formula 3 to prepare an intermediate compound having the following structure:

FORMULA 4 in which: ,R4 is selected from the group consisting of straight or branched chainlower alkyl groups having pref- .erably 1 to -6 carbon a-tom-s,'2 -thienyl, cyclopentyl, cyclol-hexyl, cycloalkyl-alkyl having '6 to 10 carbon atoms, phenyl, phenyl substituted with an alkyl group containing not in excess of .4 ca-rbonatoms and phenyl substituted with an alkoxy group containing not more than -4 carbon atoms.

The compounds of Formula 4 are readily formed by .reacting the Grignard derivative prepared from straight or branched chain lower alkyl bromides having preferably 1 to .6 carbon atoms, 'phenyl bromide, lower alkyl substituted phenyl bromide, lower alkoxy substituted phenyl bromide, 2-sbrornothiophene, cyclohexy-l bromide, cyclopentyl bromide or cycloalkyl-alkyl bromides having 6 to '10 carbon atoms with one of the esters defined in Formula '3 above. vIt is desirable to carry out-the Grignard reaction in a solvent, such as diethyl ether, using amolar excess of theGrignard reagent. The resulting amino lgetones (Formula .4) will be isolated and purified-by distillation or by the crystallizationof the organic .or inorganic acid salts from a suitable solvent. 'The intermediate amino ketone compounds of Formula 4, exceptfior-the cyclohexyl and cyclopentyl compounds, are als-oreadily formed by the reaction of the lithium derivative prepared from lower alkyl bromides, cycloalkyl- :allryl jbrornides having '6 to 10 carbon atoms, phenyl bromide lower alkyl substituted phenyl bromides, lower alkoxy substituted phenyl bromides, 2-bromothi0phene with one of the carboxylic acids defined in Formula 3 above. This reaction is carried out using a solvent such as ,di -hvlether and pref rab y p oy n nexcess of the lithium reagent.

The intermediate amino ltetone of Formula 4 can be used'to, produce the compounds of this invention, Formula 2, where R f-and R3 are the same or different as illustratedby the following scheme:

UTILITY AS INTERMEDIATBS The compounds of this invention (Formula 2) have utility, as intermediates in the preparation of the un- Saturated amines obtained by the dehydration of the tertiary alcohols .of Formula 2. The corresponding unsaturated amines can be prepared by taking the selected omp unds oLFormulaZ.and.dissolving them in, or heating it with, a mineral acid, sueh-as hydrochloric, sulfuric or phosphoric acid, organic acids such as oxalic or trichloracetic, a carboxylic acid chloride, such as acetyl chloride, a carboxylic acid anhydride, such as acetic anhydri-de, or thionyl chloride, neutralizing the reaction mixture and extracting the dehydrated product with a solvent such as ether, benzene or chloroform.

The thus formed unsaturated amines have utility, for example, for treating the parasympathetic nervous system in providing, 'for' example, anti-spasmodic and anticholinergic action and further having utility as antiemetic-s and for treating the central nervous system, for example, for treating psychotics and psychoneurotics.

This'invention will be further clarified by the following examples:

Example 1 .Di- (2-thienyl) -3-tropaneoarbinol Methyl 3-(3-acetoxytropane) carboxylate (ot-ecganjir e acetate).-A solution of 10 g. of methyl 3-(3-hydroxytropane)--car1boxylate (methyl a-ecgonine) (willstatter, Ber. 29 1575 (1 896) in 50 ml, of acetic anhydride is heated at C. for 4 hours. Theexcess acetic an- .hydride and acetic acid are removed in vacuo and the residue is poured into ice water. The mixture is saturated with potassium carbonate and the product extracted with ether. After evaporation of ether the crude methyl 3-(3- acetoxy-propane)carboxylate is purified by distillation; B. P. 16216 5 C. (15 mm); P. 66-67" C. The picrate after recrystallization from alcohol-water mixture melts at215-217.5 C.

Methyl 3-(2-tropene)carboxylate.Methyl 3-(3-acetoxytropane)-carboxylate (29 g.) is added dropwiseover a 7 min. period to a vertical Pyrex tube (25 mm. diameter), packed for a length of 8 in. with A to 4/2 in. pieces of Pyrex tubing of 7 mm. diameter, and-heated at 420 C. During the addition, the apparatus is swept out withnitrogen. The product, collected by means .of an eflicient condenser at the bottom of the tube, is dissolve yin dilute hydrochloric acid and the mixture extracted with three portions of ether. The aqueous acid solution is saturated with potassium carbonate and-the product removed by extraction with ether. Distillation of the ether solution gives methyl 3-(2-tropene car- .boxylate as a pale yellow liquid, B. P. 131-134 C.

' (15 mm); n 1.4998.

Methyl 3-tropanecarboxylata Methyl 3-(2-tropep e carboxylate (13 g.) dissolved in 100 ml. of methanol is hydrogenated over .5 g. of Raney nickel catalyst at 50 p. s. i. pressure at room temperature until hydrogen absorption ceases. Distillation of the mixture, after removal of the catalyst by filtration, gives methyl 3 tropanecarboxylate as a colorless liquid, B. P. 128-432 C. (18 mm); 21 1.4819.

Di-(2 thienyl) 3 tr0panecqrbinol..-A solution of 2,- thienyl magnesium bromide in 100 ml. of ether is prepared in the usuual way from 16.6 g. of 2-bromothiophene and 2.4 g. of magnesium. To the stirred solution, cooled to 0 C., is slowly added a solution of 6.3 g. of methyl 3-tropanecarboxylate in 20 ml. of ether. After the addition the mixture is stirred for two hours at room temperature. The mixture is cooled to 0 C., and an aqueous solution of 97 g. of the sodium salt of ethylenediamine tetraacetic acid added slowly with stirring. The ether layer is removed and the aqueous mixture is extracted with several portions of ether. Evaporation of the ether gives the crude product as a thick brown oil. The oilis dissolved in dilute hydrochloric acid and the solution extracted with two portions of ether. The acid solution is saturated with potassium carbonate and the mixture extracted with several portions of chloroform. The chloroform solution is distilled under reduced .pressure leaving a dark solid residue in the distilling flask. The solid -is dissolved in hot ethyl acetate and the solution decoloriged by boiling with charcoal. After removal of the charcoal by filtration white crystals of di-(2-thienyl)-3-tropanecarbinol separates from the cooled filtrate. The amino .carbinol melts at 157-159 C.

Example 2.--Diphenyl-3-tropanecarbin0l A solution of phenyl lithium in 100 ml. of ether is prepared in the usual way from 34.5 g. of bromobenzene and 3.5 g. of lithium. To the stirred solution cooled at C. is slowly added 10.1 g. of methyl 3-tropanecarboxylate (made following the procedure of Example 1) dissolved in 100 ml. of ether. The mixture is stirred 90 min. at room temperature and then added to 150 ml. of water. The white solid which forms is collected on a filter and washed with ether. Recrystallization of the solid from ethyl acetate gives diphenyl 3-tropanecarbinol which melts at 185.5l86 C. The picrate of the base, after recrystallization from aqueous ethanol, melts at 214-215 C.

Diphenyl-3-tropanecarbinol citrate.To 1.3 g. of the thus formed amino carbinol dissolved in 50 ml. of hot acetone is added 1.0 g. of citric acid monohydrate dissolved in acetone. The solution is concentrated and ether is added to precipitate diphenyl-3-tropanecarbinol citrate which melts at l12118 C. after recrystallization from a mixture of isopropanol and ether.

Diphenyl-3-tropanecarbin0l methobromide.--By allowing a mixture of diphenyl-3-tropanecarbinol, made as set forth above, and excess methyl bromide in acetone solution to stand for several hours at room temperature, the methobromide salt is obtained. After recrystallization from ethanol the salt melts at 309-310 C.

Example 3.1,1-di(2-thienyl) -2-(3-tr0pane) ethanol Ethyl cyano-3-tr0paneacetate.-A mixture of 13.9 g. of tropinone, 11.3 g. of ethyl cyanoacetate, 1.6 g. of ammonium acetate, 7.3 g. of acetic acid, ml. of absolute ethanol and 0.6 g. of palladium on charcoal catalyst is shaken under hydrogen at 60 p. s. i. and 50 C. Hydrogenation is interrupted when one mole equivalent of hydrogen has been absorbed. After removal of the catalyst, the solution is evaporated in vacuo on a warm water bath. The amber oily residue is dissolved in dilute hydrochloric acid and the solution is extracted with ether. The acid solution is neutralized and saturated with potassium carbonate and the product removed by extraction with ether. cyano 3-tropaneacetate as a yellow oil, B. P. 116ll8 C. (0.3 mm.); n 1.4942.

Ethyl 3-tr0paneacetate.A solution of 8 g. of ethyl cyano-3-tropaneacetate in ml. of 37% hydrochloric acid is refluxed for 13 hours. in vacuo and the residue dried by successive addition and removal by distillation of absolute ethanol. The crude 3-tropane-acetic acid hydrochloride is esterified by allowing its solution in ml. of dry ethanol saturated with hydrogen chloride to stand 3 days at room temperature. Most of the alcohol is distilled in vacuo, cold concentrated potassium hydroxide solution is added to the residue and the product removed by extraction with ether. After distillation of the solvent, ethyl 3-tropaneacetate is obtained as a colorless oil distilling at 104-105 C. (2 mm); n 1.4774.

I ,1 -di(2-thien.yl )-2-(3-Iropane) ethanol.-A solution of phenyl lithium in 100 ml. of ether is prepared in the usual way from 2.0 g. of lithium and 22 g. of bromobenzene. With stirring 11.8 g. of thiophene dissolved in 20 ml. of ether is slowly added and the resulting mixture stirred and heated at reflux temperature for 2 hours. To the mixture cooled to -20 C. is slowly added a solution of 10 g. of ethyl 3-tropaneacetate in 20 ml. of ether after which stirring is continued for 2 hours at room temperature. Ice water is added to the mixture which is then stirred vigorouslyuntil two clear layers result. From the ether layer (dried over sodium sulfate), after evaporation of solvent, l,l-di-(Z-thienyl)-2-(3-tropane)ethanol is Distillation of the ether solution gives ethyl t The solution is evaporated obtained as a solid which melts at 138140 C. after recrystallization from ethyl acetate.

1,1-di-(2-thienyl)-2-(3 lropane) ethanol acetate.The acetate salt' is precipitated by the addition of glacial acetic acid dropwise to an ether solution of the carbinol base. The white salt after being washed well with ether melts at 189-190 C.

1,1 di (2 thienyl) 2 (3 tr0pane)ethan0l methobromide.By allowing a mixture of 1,1-di-(2-theinyl)-2- 3-tropane)-ethanol and excess methyl bromide in acetone solution to stand for several hours at room temperature, the methobromide salt is obtained. After recrystallization from ethanol the salt melts at 245.5 C.

Example 4.-l,1-a'iphenyl-2-(3-tropane) ethanol To a solution of phenyl lithium in 360 ml. of ether, prepared from 94 g. of bromobenzene and 8.3 g. of lithium, cooled to 0 C. is slowly added with stirring a solution of 42 g. of ethyl 3-tropaneacetate, made following the procedure of Example 3, in ml. of ether Following the addition the mixture is stirred at 0 C. for one hour and then at room temperature for 3.5 hours. The ether solution is decanted from the solid lithium complex which forms and added with shaking to ice water. The ether layer is removed and the solvent evaporated to give solid crude 1,1-diphenyl-2-(3-tropane)- ethanol. To the solid lithium complex is added a mixture of equal volumes of ice water and chloroform and the mixture is stirred mechanically until two clear layers result. The chloroform layer is separated and the solvent evaporated to give an additional amount of the amino diphenylcarbinol. The solids from the ether and chloroform extracts are combined, washed with a small volume of ether, and recrystallized from ethyl acetate to give white crystals of pure 1,1-diphenyl-2-(3-tropane)- ethanol, M. P. l46.5-l47.5 C.

1,1-aiphenyl-2- (3-tr0pane ethanol hydrochloride-To prepare the hydrochloride of 1,l-diphenyl-2-(3-tropane)- ethanol, the amino carbinol is dissolved in chloroform and ethereal hydrogen chloride is added slowly with stirring until a slight excess of acid has been added. The mixture is then diluted with two volumes of ether and the amine salt which separates is collected on a filter. Recrystallization of the product from a mixture of alcohol and ether gives pure 1,1-diphenyl-2-(3-tropane)-ethanol hydrochloride, M. P. 234-235 C.

1,1-diphenyl-2 (3 tr0pane)ethan0l methobromide.- A solution of 1,1-diphenyl-2-(3-tropane)-ethanol in a mixture of chloroform and acetone is added to an excess of methyl bromide in acetone. After the mixture stands for several hours at room temperature, the ammonium salt which separates is collected on a filter. By recrystallization of the product from a mixture of alcohol and ether, the pure methobromide of 1,1-diphenyl- 2-(3-tropane)ethano1, M. P. 282-283" C., is obtained.

Example 5.1,1-diphenyl-2-(3-tr0pane)ethanol hydrobromide 3-tr0paneacetic acid hydrochloride-Ethyl 3-tropaneacetate, made following the procedure of Example 3', is dissolved in 37% hydrochloric acid and the solution refluxed for several hours. Evaporation of the solution to dryness in vacuo gives 3-tropaneacetic acid hydrochloride which melts at 172174 C. after recrystallization from a mixture of methanol and ether.

Phenyl 3 -tropanemethyl ketone.-A solution of phenyl lithium in 100 ml. of ether is prepared in the usual Way under nitrogen from 31.4 g. of bromobenzene and 2.8 g. of lithium. In one portion, 11 g. of 3-tropaneacetic acid hydrochloride is added and the mixture is heated to reflux temperature with stirring. The heat source is removed and the mixture allowed to reflux spontaneously until the reaction subsided. Heating and stirring are then continued for nine hours. The mixture is cooled to 0 C. and decomposed by the slow addi:

crude salt, after washing with ether, is reconverted to the base by treatment with ammonium hydroxide and extraction of the product with ether. Distillation of the ether extract under reduced pressure gives phenyl 3- t ropanemethyl ketone, B. P. 138141 C. (0.2 mm.).

1,1-diphenyl-2- (3-tropane) ethanol .hydrobromide.-An ethersolution of phenyl lithiumis prepared in the usual way from 0.7 g. of lithium and 1 6 g. of bromobenzene. To the stirred solution cooled to C. is slowlyadded an ether solution of 9 g. of phenyl 3- tropanemethyl ketone. The mixture is stirred several hours at room temperature and then poured into ice water. The resulting mixture is acidified with hydrochloric acid and the white precipitate which forms collected by filtration. Recrystallization of the solid from a mixture of ethanol and ether gives the hydrobromide salt of 1,1-

diphenyl-Z- 3-tropane) ethanol which melts at 230 6. Example 6 .1 -phenyl-1 (Z-thienyl) -2-(3-tropane) ethanol A solution of phenyl lithium in 100 ml. of ether is canted from the solid lithium complex which formed and added with shaking to ice water. The the'layer is removed and the solvent evaporated to give solid crude 1-phenyl-l-(2-thienyl) 2 (3 tropane)ethanol. To the solid lithium complex is added a mixture of equal volumes of ice water and chloroform and the mixture is stirred mechanically until two clear layers result. The chloroform layer is separated and the solvent evaporated to give an additional amount of the amino thienylcarbin'ol. Recrystallization of the crude product from ethyl acetate solution decolorized by charcoal gives white crystals of 1-pheny1-1-(2-thienyl) 2 3 tropane)ethanol melting at 137.5139 C.

I -phenyl-1 -(2-thienyl) 2 (3 tropanflethanol maleate.-Addition of the thus preparedcarbinol base to an equimolecular amount of maleic acid in acetone solution gives the maleate salt as white crystals melting at 145-146 C. after recrystallization from ethanol-ether.

1-phenyl 1 -(2-thienyl) -2 (3 tr0pane)ethanol metho bromide-By allowing a mixture of '1-phenyl-1-(2-thienyl) -2-(3-tropane) -ethanol and excess methyl bromide in acetone solution to stand for several hours at room temperature, the methobromide salt is obtained. After recrystallization from ethanol the salt melts 31225.6

Example 7. 1-phenyl-1-(Lpyridyl)-2-(3 tr0pane) ethanol A solution of n-butyl lithium in 25 ml. of ether is prepared in the usual Way from 3.7 g. of n-butyl chloride and 0.7 g. of lithium. With stirring the solution is cooled to --45 'C. and 5.5g. of 2-bromopyridine dissolved-in ml. of ether is added slowly. After the addition, the mixture is stirred 10 minutes and 2.5 g. of phenyl 3-tropanemethyl ketone (prepared following'the procedure of Example 5) dissolved in 30 ml. of ether is added slowly. The mixture is then stirred minutes at 15 C. Water (50 ml.) is added slowly and the mixtureis stirred vigorously for 15 minutes. A yellow solid forms which'is collected on a filter and Washed with ether. The ether layer in the filtrate is separated and saved. The solid is stirred vigorously in a mixture of equal volumes of chloro- -form'.1and water. untiLtwo clear layersresult. The chlorotform layer is removed and combined with the ether solution above. Evaporation of the-solvents in vacuo gives -.a yellow oil which crystallizes when-stirred with ether. :By recrystallization of :the product from ethyl acetate 1- phenyl-l-.(.2-pyridyl)-2- (-3-tropane)ethanol is obtained as .whitecrystals melting at 117-1185 C.

:1.- phenylle(2-pyridyl -2-(3-tr0pane) ethanol hydroiodide.-To an .ethanolic solution of the thus prepared carbinol base is added dropwise 57% hydriodic acid untilno more fuming occurs. ,Addition of a mixture of acetone .and ether to thesolution, precipitates the hydriodide'salt .as a white gummy solid whichbecomes crystalline when .triturated with ether. Analysis of the product, M. -P. 194-l96 C., shows it to be the monohydroiodide saltof the carbinol base.

1 -phenyl-1 (Z-pyridyl) -2-(3-tr0pane) ethanol methobromide-By allowing a mixture of the carbinol base prepared above andexcess methylbromide in acetone solutionto stand for several hours at room temperature-a methobromide salt is obtained which melts at 268 C. after recrystallization from ethanol. Analysis of the productshows it to he the monomethobromide salt of the carbinol base.

Example 8.1-ethyl-I-phenyl --2- (S-tropane) ethanol A solution'of ethyl magnesiumbromide in 200 ml. of ether is prepared from 7.3 goof magnesium and 32.7 g. of ethyl bromide in the usual 'way. While the solution is stirred and cooled at 0 C., 12.2 g. of phenyl 3-tropanemethyl ketone, prepared following the procedure of'Example :5, dissolved in 50 ml. of ether is added slowly. Thereaction mixture is stirred 1.5 hours at-room temperature and'then 1.5 hoursat reflux temperature after which time it isdecomposed by addition to a mixture of cracked ice and 21 g. of ammonium chloride in '50 ml. of water. The ether layer is'removed and the aqueous phase extracted twice with chloroform. Evaporation of solvents from the combined extracts gives an oily residue which yields, when stirred with ether, 1-ethyl-1-phenyl-2-(3- tropane)ethanol as a white powder melting at 119-1 20 C. From the'filtrate from the solid is recovered the starting material, phenyl 3-tropanemethyl ketone.

1 -ethyl-1 -phenyl-2- (3-tropane) ethanol hydr0chl0riae. Treatment of l-ethyl-l-phenyl-2-(3-tropane)ethanol dissolved in ether with ethereal hydrogen chloride solution yields the hydrochloride salt which melts at 237-237. 5' C. after recrystallization from ethanol.

Example 9.1-cycl0hexyl- 1-phenyl-2- (3-lropane) ethan.0l

Cyclohexyl 3-tr0panem-ethyl ketone.-A solution of cyclohexyl magnesium bromide in 700 ml. of ether ,is prepared in the usual way from 11.5 g. of magnesium and 77 g. of cyclohexyl bromide. To the stirred solution cooled to 0 C. is added slowly 25 g. of ethyl 3-tropaneacetate (made following the procedure of Example 3) dissolved in 45 ml. of ether. The mixture is stirred at 0 C. for 0.5 hr. and then heated at the reflux temperature for 5 hours. The mixture is again cooled to 0 C. and a solution of 483 g. of the sodium salt of ethylenediamine-tetraacetic acid in 590 ml. of water is added slowly with stirring. The ether layer-is removed and the aqueous mixture is extracted with several portionsof ether. Distillation of the ether solution under reduced pressure gives cyclohexyl -3-tropanemethyl ketone boiling at 142-15 3 C. (0.810 1.1-1pm.). The distilled product crystallizes to a White solid on standing.

1 cyclohexyl-1-phenyl-2-(3-tr0pane)ethanol.-A solution of phenyl lithium in 130 ml. of etheris prepared in the usual way from 1.6 g. of lithium and 18 g. of bromobenzene. With stirring 10 g. of cyclohexyl 3-tropanemethyl ketone dissolved in 40 ml. of etheris slowly added to the solution cooled to 0 C. The mixture is stirred 20 minutes at 0 C. and then heated at the reflux temperature for 5 hours. Ice water ml.) is slowly added of chloroform and water for 30 minutes and the chloroform layer is separated. The ether layer of the filtrate from the solid is combined with the chloroform solution and the solvents are removed in vacuo to give solid crude l cyclohexyl-1-phenyl-2-(3-tropane)ethanol. After two vrecrystallizations of the solid from ethyl acetate, the pure product, melting at 139140.5 C., is obtained.

I-cyclohexyl-l-phenyl-2-(3-tr0pane)ethanol hydrochloride-Addition of ethereal hydrogen chloride to an ether solution of a portion of the thus prepared carbinol base gives the hydrochloride salt as a white crystalline solid. After two recrystallizations from ethanol ether, the salt melts at 254-255" C.

1 cyclohexyl I-phenyl 2-(3-tropane)-ethan0l methobrmide.By allowing a mixture of the portion of the .thus prepared carbinol base and excess methyl bromide .in acetone solution to stand for several hours at room temperature, the methobromide salt is obtained. The salt, after recrystallization from ethanohether, melts at 262 C.

Example 10.-1.- (2 cyclohexylethyl) I phenyl 2-(3- tr0pane)ethan0l 2-cyclohexylethyl 3-tr0panemethyl ket0ne.An ether solution of 2-cyclohexylethyl magnesium bromide is prepared in the usual way from 7 g. of magnesium and 51.8 g. of cyclohexylethyl bromide. To the stirred solution cooled to 0 C. is added slowly g. of ethyl 3-tropaneacetate (prepared following the procedure of Example 3) dissolved in 30 ml. of ether. The mixture is stirred at 0 C. for 0.5 hr. and then at room temperature for 2.5 hours. The mixture is again cooled to 0 C. and a solution of 290 g. of the sodium salt of ethylenediamine tetraacetic acid in 345 ml. of water added slowly with stirring. The-ether layer is removed and the aqueous mixture extracted with several portions of ether. Distillation of the ether solution under reduced pressure gives 2-cycl0hexylethyl 3-tropanemethyl ketone; B. P. 157164 C. (0.7 mm.); r1 1.5010. The picrate of the base melts at 148-150" C. after recrystallization from dilute ethanol.

1 (2 cyclohexylethyl) 1 phenyl 2 (3 tropane) ethan0l.A solution of phenyl lithium in 75 ml. of ether is prepared in the usual way from 0.8 g. of lithium and 9.4 g. of bromobenzene. With stirring 7.7 g. of 2-cyclohexylethyl 3-tropanemethyl ketone dissolved in ml. of ether is slowly added to the solution cooled to 0 C. The mixture is stirred one hour at 0 C. and 3 hours at room temperature. Ice water is then slowly added and the resulting mixture stirred vigorously for minutes. The ether layer is separated and the aqueous layer extracted with ether. On evaporation of the ether solution (dried over sodium sulfate) a. clear oil is obtained which crystallizes when stirred with a small volume of petroleum ether. Recrystallization of the white solid from ethyl acetate gives transparent crystals of 1-(2-cyclohexylethyl)- l-phenyl-Z-(3-tropane)-ethanol melting at 104-106 C.

l (2 cyclohaxylethyl) 1 phenyl 2 (3 tropane) ethanol hydrochloride.-T 1e hydrochloride salt of the base, precipitated from ether solution, melts at 215-2l6 C. after recrystallization from a mixture of ethanol and ether.

I (2 cyclohcxylezhyl) 1 phenyl 2 (3 tropane) ethanol citrate-By addition of an equimolecular portion of citric acid to an'acetone solution of the'carbinol base, the citrate salt is obtained as a white powder. After two recrystallizations from acetone-methanol, the salt melts at l34l36 C.

I (2 cyclohexylethyl) I phenyl 2 (3 tropane) ethanol methobronzide.-By allowing a mixture of the carbinol base and excess methyl bromide in acetone solution to stand for several hours at room temperature, the methobromide salt, P. 263-2 65 C., is obtained;

' Example 11.1'-(p-tinisyl)-1-phenyl-2-[3 (N-isopr0pyl nortropime) l-ethanol Methyl 3-(N-isopropylnorti'opune) acetate-A mixture of 16.7 g. of N-isopropylnortropanone, 11.3 g. of ethyl cyanoacetate, 1.6 g. of ammonium acetate, 7.3 g. of acetic acid, 20 ml. of absolute ethanol and 0.6 g. of palladium on charcoal catalyst is shaken under hydrogen at 60 p. s. i. and60 C. Hydrogenation is interrupted when one mole equivalent of hydrogen has been absorbed. After removal of the catalyst, the solution is evaporated in vacuo on a warm water bath. The oily residue is dissolved in concentrated hydrochloric acid and the solution is extracted with several portions of ether. The

aqueous acid solution is refluxed 12 hours, evaporated in vacuo, and the residue is dried by successive addition and removal by distillation of dry benzene. The crude 3-(N-isopropylnortropane)acetic acid hydrochloride ,so obtained isesterified by allowing its solution in' l0 0 ml; of anhydrous methanol saturated with hydrogen chloride to stand 3 days at room temperature. Most of the methanol is distilled under reduced pressure, cold concentrated potassium hydroxide solution is addedto the residue, and the product is removed by extraction with ether. Distillation of the ether solution in vacuo gives methyl 3-(N-isopropylnortropane)acetate as a colorless oil distilling at 124-127 C. (0.3 mm). I

p-Anisyl 3-(N-isopropylnortropane)methyl ket0ne.A solution of p-anisyl magnesium bromide in 200ml. of ether is prepared from 28 g. of p-bromoanisole and3.7 g. of magnesium in the usual way. The solution is cooled to 0C. and 11.3 goof methyl 3-(N-isopropylnortropane) acetate dissolved in 25 ml. of ether is added slowly with stirring. After the addition the mixture is stirred for'one hour at room temperature and is then heated at reflux temperature for 2 hours. The mixture is cooled to 0 C. and a solution of g. of the sodium salt of ethylenediamine tetraacetic acid in 180 ml. of water is added slowly with stirring. The other layer is removed and the aqueous layer is extracted with two portions of chloroform. Evaporation of the solvents from the combined extracts gives the crude product as a thick oil which is purified by distillation under reduced pressure. p-Anisyl 3-(N-isopropylnortropane)-methyl ketone obtained in this way boils at -l64 C. (0.2,mm.) and crystallizes as a white solidupon standing.

I -(p anisyl) I phenyl 2 [3 (N isopropyle nortropane)l-ethanoL-To a solution of phenyl lithium in 45 ml. ether, prepared in the usual way from 7.9 g. of bromobenzene and 0.7 g. of lithium, is slowly added with stirring at 0 C. a solution of 7.5 g. of p-anisyl Z-(N-isopropylnortropane)methyl ketone in 20 ml. of ether. Following the addition the mixture is stirred at 0 C. for one hour, and then at room temperature for four hours. Water,(50 ml.) is then added and the mixture is stirred, vigorously for 2 hours. The ether layer is removed and the aqueous mixture is extracted with two portions of chloroform. Evaporation of the solvents from the combined extracts gives a crystalline residue of crude prod uct which is purified by recrystallization from ethyl acetate. In this way, 1-(p-anisyl)-l-phenyl-2-[3-(Nisopropylnortropane) ]-ethanol is obtained as a white crystalline solid.

Example.12. I,1-diphenyl-3-(3-tr0pane)pr0pan0l 'Ethyl fl-(3-tr0pane)pr0pi0nate.-To a suspension of 3.7.

g. of 3-tropaneacetic acid hydrochloride (prepared fol-.

lowing the procedure of Example 5) in 30 ml. of chloroform is added 4.7 g. of thionyl chloride and the resulting mixture is heated at reflux temperature for 2.5 hours. The solvent and excess thionyl chloride are evaporated in vacuo and the last traces of the latter are removed from the solid residue by successive addition and removal by distillation in vacuo of two 50 ml. portions of benzene. In this way, theacid chloride hydrochloride is obtained as a brown powder.

The acid chloride hydrochloride is suspended in 30 ml. of methylene chloride and the mixture added in por tions to a solution of diazomethane, prepared in the usual way from 14.7 g. of N-methyl-N-nitroso-N'-nitroguanidine, in 200 m1. of methylene chloride kept at C. After storage of the mixture at room temperature for two hours, the solvent is evaporated in vacuo to give diazomethyl 3-tropanemethyl ketone as a hygroscopic brown powder.

The diazo ketone is dissolved in 35 ml. of absolute ethanol and the solution maintained at 5060 C. while a suspension of silver oxide, freshly prepared from ml. of 10% silver nitrate solution, in 30 ml. of dry ethanol is added over a 45 min. period. After the addition the mixture is refluxed for 30 min. and then filtered. By distillation of the filtrate in vacuo, ethyl fl-(3-tropane) propionate is obtained.

1,1-diphenyl-3-(3-tropane)propanol.-A solution of phenyl lithium in 500 m1. of ether is prepared in the usual way from 75 g. of bromobenzene and 6.7 g. of lithium. To the stirred solution is slowly added 18 g. of ethyl .B-(3-tropane)propionate dissolved in 50 ml. of ether. The mixture is stirred and heated at reflux temperature for 3.5 hours. After cooling 50 ml. of water is added and the mixture stirred vigorously for one hour. The ether layer is removed and the aqueous layer which contains a white solid is shaken vigorously with chloroform. The chloroform layer is separated, combined with the ether solution and the solvents are evaporated in vacuo. In this way, 1,l-diphenyl-3-(3 tropane)propanol is obtained .as a white .crystalline solid melting at l4l 142.5 C.

1,1-diphenyl-3-v(3-tropane) propanol hydrochloride-A portion of thecarbinol base dis-solved in ether .is neutralized with hydrogen chloride to give 1,1-diphenyl-3- (3-tropane)propanol hydrochloride. The salt, after recrystallization from a mixture of methanol and ether, melts at 249-250 C.

1,1-diphenyl-3-(3-lropane)propanol meth0br0mide.- The methobromide salt of 1,l-diphenyl-3-(3-tropane)- propanol is prepared as described in Example 6. The

quaternary salt melts at 299 C.

Example 13..-1-ethyl-1-(Z-pyridyl)-3-(3-tr0pan.e)-

propanol Ethyl .fi-(3-tropane)ethyl ketone.-A solution of ethyl magnesium bromide in 35 ml. of ether is prepared in the usual way from 1.3 g. of magnesium and 6.4 g. of ethyl bromide. To the stirred solution, cooled to 0 C., is slowly added .3 vg. ofethyl v iti-(i-tropane.)propionate (prepared following the procedure of Example 12) dissolved in 30 ml. of ether. The mixture is stirred 4 hours, then cooled :to .0" C. and a solution of g. of the sodium salt of ethylenediamine tetraacetic acid'in 58 ml. .of water is slowly added. The ether layer is removed and the aqueous phase is extracted with several portions of ether. Distillationof the ether extracts under reduced pressure gives ethyl fl- ('3-tropane)ethyl ketone as :a colorless liquid; B. P. 105-109 (0.35 mm); 12 1.4870. The .picrate of 'the amino ketone melts ,at 123-1245 C. after :recrystallization from alcohol.

1 -'eth yl-1'- 2-pyridyl -3-(3-tr0pane propan0l.-A solution of n-butyl lithium in 15 ml. of etheris-prepared in the usual .way from 1.9g. of n'-.butyl chloride and 0.35 g. of lithium. With stirring the solution -is cooled to -45 C. and 2.8g. of 2-bromopyridine dissolvedin 5 :ml. of etherris added slowly. After-the addition the mixture is stirred 10 minutes and 1.1 g. .of-ethyl B-(B-tropane} ethyl ketonedissolved in 15 ml. .of ether is added slowly. Themixture is-then-stirred 15 minutes at 15.C. Water (25 ml.) -is added slowlyand the mixture is stinred vigorous'ly for 45 minutes. The ether layer isremoved and the aqueous phase is stirred vigorously with an equal volume of chloroform until two clear layers result. By evaporation in vacuo of thesolvents from the combined extracts the product is obtained as "a yellow oil which 14 crystallizes when stirred with a small volume of epic! ether. Recrystallization of the product from ethyl acetate gives 1 ethyl-l-(2-pyridyl)-3-(3-tropane)propanol as a white crystalline solid.

3-(3-tropane)pr0par ol.-To a stirred solution of 3 ,g. of lithium aluminum hydride in 200 ml. of ether isadded a solution of 17.8 g. of ethyl p-(3-tropane)propionate (prepared as in Example 12) in 50 m1. of ether at such a rate that steady reflux of ether is maintained. After the mixture is stirred at reflux temperature for three hours, it is cooled at 0 C. and 7.2 ml. of water is added gradually. Theresulting mixture is stirred for two hours, filtered and the collected solid is washed with ether. "Distillation of the ether solution in vacuo gives 3-(3-tropane)- propanol boiling ,at 128-131 C. (2 mm.).

- 1- hloro-3-(3-tropane)propane.-r-To a solution of 7.7 g. of 3-(3-tropane)propanol in 30 ml. of .chlorofrom is slowly added 1.0 g. of thionyl chloride. The reaction mixture is heated at gentle reflux for.45 minutes and then evaporated to dryness in vacuo. The residue of crude 1-ch1oro-3-(3-tropane)propane hydrochloride is treated with potassium carbonate solution and the oily base which forms is extracted with ether. Distillation of the ether solution gives l-chloro-3-(3-tropane)propane boiling at -l02 C. (1 mm).

'y-(3 tropane)butyr0nitrzfle.'.-lchloro 3 (3 pane)propane (5 g.) and 0.1 g. of sodium iodide is added to a solution of 5g. of potassium cyanide in a mixture of 18 ml. of alcohol and 8 of water. The resulting solution is heated at reflux temperature for 18 hours and then evaporated "in vacuo. Sodium hydroxide solution is added to the residual mixture of oil and solid and, the oil is separated by extraction with ether. Distillation of the ether solution under reduced pressure gives '7-(3-110- pane)bu tyronit rile boiling at 132.135 (0.3 mm).

Ethyl {Y-(3-tr0pane)butyrate.- -A solution of 3 g. of 'y-(3-tropane)Fbutyronitrile in 15' ml. of 37% hydrochloric acid is heated at reflux temperature for several hours and then evaporated to dryness in vacuo. The solid residue is dissolved in 35 ml. of absolute ethanol, 0.5 ml. of concentrated sulfuric acid is added, and the resulting solution is heated at reflux temperaturefor 7 hours. The mixture is concentrated in vacuo and the residue is treated with 40% sodium hydroxide'solution. The oil which separates ,is removed by extraction with ether and purified by distillation under reduced pressure. In this way, ethyl 'y-(3-tropane)-but yra te distilling at 115419 C. (0.5 mm.) is obtained.

P-Tolyl 'y-.(3-tropane)propyl ket0ne..A solution of p-to'lyl magnesium bromide in 40 ml. of ether is prepared inthe usual way from 5.1 g. of p-bromotoluene and 0.75 g. of magnesium. To the stirred solution, cooled to0 C., is slowly added a solution of 2.3 g. of ethyl 7-(3-llf0- pane)butyrate in ,10 ml. of ether. After the addition the mixture is stirred at room temperature for one hour and then at reflux temperature for 2 hours. The mixture is cooled to 0 C. and a solution of 27 g. of the sodium salt of ethylenediaminetetraacetic acid in 36 ml. of water is added slowly with stirring. The etherlayer is removed and :the aqueous layer is extracted with severalportions of ether. Distillation .of theether extracts under reduced pressure gives p-tolyl. 1(3.-tropane)propyl'ketone boiling at 188-192 C. 0 .2 mm.).

1 --(-2 pyridyl) -;1-- p.- Zolyl 4.- (3 tropane-Mu? tanol. A solution ,of-n-butyl lithium in 15 ml. vof ether is prepared in theusual way from 1.9 g. of n-butyl chloride and 0.35 g. of lithium. With stirring the solution is cooled to 4 5 C. and 2.8 g. of 2-bromopyridinedissolved in '5 ml. of ether is added slowly. Afterthe addition themixture is stirred 10 minutes and 1.5 g. of ptolyl -(j3-tropane )propyl ketone dissolved .in 15 of ether is added slowly. .The mixture is then stirred 15 minutes at l5 C. Water ('25 ml.) is added slowly and the mixture is stirred vigorously for 30 minutes. The etherlayer is removed and the aqueous layer is stirred vigorously with an equal volume of chloroformuutil two clear layers result. Evaporation invacuo' of the solvents from the combined ether and chloroform solutions gives a yellow oil which crystallizes when stirred with a mixture of ether and petroleum ether. By recrystallization of the product from a mixture of ethyl acetate and petroleum ether 1-(2-pyridyl)-1-p-tolyl-4-(3-tropane)butanol is obtained as a white crystalline solid.

Example I5.- Dimethyl-.i-tropanecarbinol.

. Dimethyl-3-tropanecarbinol.--A solution of methyl lithium in 150 ml. of ether is prepared in the usual way from 28.4 g. of methyl iodide and 2.8 g. of lithium. To the solution cooled to C. is added slowly with stirring a solution of 9.2 g. of methyl 3-tropanecarboxylate (prepared following the procedure of Example 1) in 30 ml. of ether. After the addition the mixtureis stirred at 0 C. for one hour and then heated at reflux temperature for 3 hours. The mixture is cooled to 0 C. and decomposed by slow addition of 50 ml. of water. The ether layer is removed and the aqueous phase is stirred vigorously with an equal volume of chloroform until two clear layers result. By evaporation of the combined extracts in vacuo dimethyl-3-tropanecarbinol is obtained as a yellow oil which crystallizes as a white solid when stirred with a small volume of ether.

Example 16.--I,1 di N hexyl 2 [3 (N isopropylnortropaneflethanol Methyl 3-(N-isopropylnortropane)acctate. -A mixture of 16.7 g.. of N-isopropylnortropinone, 11.3 g. of ethyl cyanoacetate, 1.6 g'. of ammonium acetate, 7.3 g. of acetic acid, 20 ml. of absolute ethanol and 0.6 g. of palladium on charcoal catalyst is shaken under hydrogen at 60 p. s. i. and 60 C. Hydrogenation is interrupted when one mole equivalent of hydrogen has been absorbed. After removal of the catalyst, the solution is evaporated in vacuo on a warm water bath. The oily residue is dissolved in concentrated hydrochloric acid and the solutiori is extracted with several portions of ether. The aqueous acid solution is refluxed 12 hours, evaporated in vacuo, and the residue is dried bysuccessive addition and removal by distillation of dry benzene. The crude 3- (N-isopropylnortropane) acetic acid hydrochloride so obtained is esterified by allowing its solution in 100 ml. of anhydrous methanol saturated with hydrogen chloride to stand 3 days at room temperature. Most of the methanol is distilled under reduced pressure, cold concentrated potassium hydroxide solution is added to the residue, and the product is removed by extraction with ether. Distillation of the ether solution in vacuo gives methyl 3-(N-isopropylnortropane)-acetate as a colorless oil distilling at 124-127 C. (0.3 mm.).

1,1 di n hexyl 2 [3 (N isopropylnortropane)]ethan0l.A solution of n-hexyl lithium in 150 ml. of ether is prepared in the usual way from 33 g. of n-hexyl bromide and 3 g. of lithium. To the solution cooled to 0 C. is added slowly with stirring a solution of 11.3 g. of methyl 3-(N-isopropylnortropane)-acetate (made following the above procedure) in 40 ml. of ether. After the addition the mixture is stirred at 0 C. for one hour and then heated at reflux temperature for 3 hours. The mixture is cooled to 0 C. and decomposed by slow addition of 50 ml. of water. The ether layer is removed and the aqueous phase is stirred vigorously with an equal volume of chloroform until two clear layers result. By evaporation of the combined extracts in vacuo and stirring the residual oily residue with cold petroleum ether, 1,1- di-n-hexyl-2-[3-(N-isopropylnortropane)lethanol is. ob tained asawhite crystalline solid.

Example 17.] cyclopentyl 1 phenyl 4 (3 tropane)butan01 3-(3-tr0pane)propan0l.-T0 a stirred solution of 3 g. of lithium aluminum hydride in 200 ml. of ether is added a solution of 17.8 g. of ethyl B-(3-tropane)propionate prepared as in Example 12, in 50 ml. of ether at such a rate that. steady reflux of ether is maintained. After the mixture is stirred at reflux temperature for three hours, it is cooled to 0 C. and 7.2 ml. of water is added gradually. The resulting mixture is stirred for two hours, filtered and the collected solid is washed with ether. Distillation of the other solution in vacuo gives 3-(3-tropane)propanol boiling at 128-131 C. (2 mm.).

1-chlor0-3-(3-tropane)propane.To a solution of 7.7 g. of 3-(3-tropane)propanol in ml. of chloroform is slowly added 10 g. of thionyl chloride. The reaction mixture is heated at gentle reflux for 45 minutes and then evaporated to dryness in vacuo. The residue of crude 1-chloro-3-(3-tropane)propane hydrochloride is treated with potassium carbonate solution and the oily base which forms is extracted with ether. Distillation of the ether solution gives 1-chloro-3-(3-tropane)propane boiling at 100-102 C. (1 mm.).

'y-(3-tropane)butyronitrile. 1-chloro-3-(3-tropane) propane (5 g.) and 0.1 g. of sodium iodide is added to a solution of 5 g. of potassium cyanide in a mixture of 18 ml. ofalcohol and 8 ml. of water. The resulting solution is heated at reflux temperature for 18 hours and then evaporated in vacuo. Sodium hydroxide solution is added to the residual mixture of oil and solid and the: oil is separated by extraction with ether. Distillation of the ether solution under reduced pressure gives 7 (3- tropane)butyronitrile boiling at-l32-135 (0.3mm).

Ethyl 'y-(3-tr0pane)butyrate.A solution of 3 g. of 'y-(3-tropane)-butyronitrile in 15 ml. of 37% hydrochloric acid is heated at reflux temperature for three hours and then evaporated to dryness in vacuo. The solid residue is dissolved in ml. of absolute ethanol, 0.5 m1. of concentrated sulfuric acid is added, and the resulting solution is heated at reflux temperature for 7 hours. The mixture is concentrated in vacuo and the residue is treated with 40% sodium hydroxide solution. The oil which separates is removed by extraction with ether and purified by distillation under reduced pressure. In this way, ethyl 'y-(3-tropane)-butyrate distilling at 115-119 C. (0.5 mm.) is obtained.

Cyclopentyl 3-(3-tropane)propyl k'et0ne.-A solution of cyclopentyl magnesium bromide in 35 0 ml. of ether is prepared'in the usual way from 5.8 g. of magnesium and 37 g. of cyclopentyl bromide. To the stirred solution cooled to 0 C. is added slowly 14.3 g. of ethyl 7-(3- tropane)butyrate (prepared by the above procedure) dissolved in 30 m1. of ether. The mixture is stirred'at 0 C. for one hour and then heated at reflux temperature for 3 hoursf The mixture is then cooled to 0 C. and a solution of 242 g. of the sodium salt of ethylenediamine tetraacetic acid in 300 ml. of water is added slowly with stirring. The ether layer is removed and the aqueous phase is extracted with several portions of ether. Distillation of the ether extract under reduced pressure gives cyclopentyl 3-(3-tropane)propyl ketone boiling at 152- 156 C. (0.8 'mm.').

1-cyclopentyl-1-phenyl-4 (3- tropane) butan0l. -A solution of phenyl lithium in ml. of other is prepared in the usual way from 11.8 g. of bromoben zene and 1.1 g. of lithium. To the solution cooled to 0 C. is added slowly with stirring a solution of 6.6 g. of cyclopentyl 3-(3-tropane)propyl ketone (made as above) in 25 ml. of ether. After the addition the mixture is stirred at 0 C. for one hourand then heated at reflux temperature for 3 hours. The mixture is cooled to 0 C. and decomposed by slow addition of 20 ml. of water. The ether layer is removed and the aqueous phase is stirred vigorously with an equal volume of chloroform until two Example 18.Diphenyl 3-tropanecarbin0l ethoethylsulfate By heating a mixture of one gram of diphenyl S-tropanecarbinol, made as in Example 2, and excess diethyl sulfate in acetone solution at reflux temperature for hours, the quaternary ammonium salt is obtained as a white solid.

Example 19.-1,1-diphenyl-2- (3-tropane)ethanol metho-ptoluenesulfonate Example 20.1,1-diphenyl- -(3-tropane)ethanol ethoethylsulfate By heating a mixture of one gram of 1,1-diphenyl-2-(3- tropane)ethanol, made as in Example 4, and excess diethylsulfate in acetone solution at reflux temperature for 5 hours the quaternary ammonium salt melting at 234- 235 C. is obtained.

Example 21 .-1,1-diphenyl-2-(3-tropane)ethanol butylbromide By heating a mixture of one gram of 1,1-diphenyl-2- (3-tropane)ethanol, made as in Example 4, and excess butyl bromide in acetone solution at reflux temperature for 20 hours, the quaternary ammonium salt melting at 225-227 C. is obtained.-

Example 22.1,1-diphenyl-2- (3-tropane) ethanol butyliodide By heating a mixture of one gram of 1,1-dipheuyl-2-(3- tropane)-ethanol, made as in Example 4, and excess butyl iodide in acetone solution at reflux temperature for 5 hours the quaternary salt melting at 227-229 C. is obtained.

Example 23.-1-cyclohexyl-I-phenyl-2- (3-tr0pane) ethanol butyl-bromide By heating a mixture of one gram of l-cyclohexyl-lphenyl-Z-(3-tropane)ethanol, made as in Example 9, and excess butyl bromide in acetone solution at reflux temperature for 20 hours the quaternary ammonium salt is obtained as a white solid.

The compounds of Formulas 3 and 4 and the dehydration products of the compounds of this invention are the subject-matter of my copending applications Serial No. 519,647, filed July 1, 1955; Serial No. 519,648, filed July 1, 1955; and Serial No. 519,650, filed July 1, 1955, respectively and reference may be made thereto for further examples of these compounds as well as for methods of their preparation.

It is not desired to be limited except as set forth in the following claims.

What is claimed is:

1. Compounds of the class consisting of a free base and the acid addition and quaternary ammonium salts thereof, the free base having the following formula:

OH RN (0H2) n 3 in which R is a lower alkyl radical, n is from 0 to 2, and R2 and Rs are selected from the group consisting of lower alkyl, cycloalkyl having from 5 to 6 carbon atoms, cycloalkyl alkyl having 6 to 10 carbon atoms, 2- thienyl, Z-pyridyl, phenyl, phenyl substituted with an alkyl group having 1 to 4 carbon atoms and phenyl substituted with an alkoxy group having 1 to 4 carbon atoms.

2. 1,1-diphenyl-2-(3-tropane) ethanol.

3. Diphenyl-3-tropanecarbinol.

4. 1,1-di-(2-thienyl)-2-(3-tropane)ethanol.

5. l-phenyl-l-(2-thienyl)-2-(3-tropane)ethanol.

6. l-cyclohexyl-l-phenyl-Z-(3-tropane)ethanol.

No references cited. 

1. COMPOUNDS OF THE CLASS CONSISTING OF A FREE BASE AND THE ACID ADDITION AND QUATERNARY AMMONIUM SALTS THEREOF THE FREE BASE HAVING THE FOLLOWING FORMULA: 